Abstract Extensive research on the basic immunological mechanisms that drive human immunity has provided the general framework by which the human immune system responds to foreign antigens. However, it is well-appreciated that each viral infection poses unique challenges to the immune system and the elicited immune responses are characterized by substantial heterogeneity that impacts disease susceptibility and pathogenesis, by conferring either protective or disease-enhancing activities. The ongoing COVID-19 pandemic represents a significant threat for global public health with tremendous socio-economic consequences. Early clinical and epidemiological data from COVID-19 patients suggest that while for the majority of the population, SARS-CoV-2 infection causes mild symptoms that usually resolve within a few weeks, a substantial fraction of patients develops severe, often life-threatening, clinical complications, including acute respiratory distress syndrome and pneumonia. Differences in the induction of protective antiviral immunity likely accounts for the differential susceptibility to severe disease upon SARS-CoV-2 infection. Understanding the heterogeneity of immune responses elicited upon SARS-CoV-2 infection is therefore critical for characterizing the immune mechanisms that confer protection against COVID-19 disease, guiding the development of novel therapeutics for disease control, as well as, determining disease susceptibility in high-risk populations. The proposed studies aim to characterize the antibody responses that are elicited upon infection with SARS-CoV-2, determining the breadth of antibody specificities, neutralization potency, as well as Fc domain heterogeneity of anti-SARS-CoV-2 IgG antibodies. More specifically, we plan to recruit recovered COVID-19 patients and systematically analyze their B-cell responses to determine their transcriptomic profile, as well as the functional properties of their B-cell receptors. In parallel, serologic studies from these individuals aim to characterize the breadth and potency of their neutralization activity and determine the subclass and Fc glycan distribution of anti-SARS-CoV-2 antibodies. Additionally, Fc domain function will be assessed in well-established ADCC, ADCP, and ADE assays to evaluate the capacity of anti-SARS-CoV-2 IgG antibodies to confer protective or pathogenic activities. Follow-up serologic studies will be performed in a large cohort of patients with variable disease severity, ranging from asymptomatic to severe symptomatic cases, to determine the functional activity of elicited anti-SARS-CoV-2 antibodies and assess their Fc domain heterogeneity and effector function. These studies are within the scope of our parent grant, as they are focused on the understanding of the immune responses that are elicited during viral infection. We anticipate that the findings of these studies will provide novel insights into the immunological mechanisms that confer protection or susceptibility to COVID-19 disease, accelerating our efforts for the development of vaccine or therapeutic interventions for the control of SARS-CoV-2 infection.